Rheumatoid arthritis (RA) is a systemic inflammatory disease that leads to progressive joint destruction, disability, and accelerated mortality. Factors that influence autoantibody production and disease severity in RA have not been fully defined. However, there is increasing data showing that cigarette smoking, associated with disease susceptibility, is also associated with RA outcomes and its effect is likely modified by HLA-DRB1 alleles encoding the shared epitope (SE). Studies examining RA severity have focused on the interaction of smoking primarily with SE in groups that have exclusively included Caucasian women. This is important because smoking, in terms of RA risk has its greatest impact in men while other smoking related illnesses disproportionately impact non-Caucasians. There is increasing data that genetic variation in CD14 and Toll-like receptors (TLRs) (pattern recognition receptors found on inflammatory cells) may explain variability in the expression of other inflammatory/autoimmune conditions and may be particularly important in the context of smoking. We will examine determinants of autoantibody production and disease severity in 1300 subjects (including ~1040 Caucasians) from VARA cohort and 680 African Americans (~500 from CLEAR and ~180 from VARA). The overall hypothesis of this study is that variation in genes encoding CD14/TLRs will mediate the detrimental effect of smoking on RA-specific autoantibody production, disease severity, and the prevalence of extra-articular disease (most notably, rheumatoid nodules and lung involvement). The aims of this study are to examine: 1) the associations of genetic variation in CD14/TLR with disease-specific autoantibody production and measures of RA disease severity and 2) the interactions between cigarette smoking and genetic variation in CD14/TLR as determinants of disease-specific autoantibody production and RA disease severity. In addition to genetic polymorphisms of CD14/TLR genes, factors to be studied will include SE and protein tyrosine phosphatase (PTPN22), well characterized risk factors for RA. RA- specific outcomes that will be examined include radiographic measures (modified Sharp score), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, and extra-articular disease (nodules and lung involvement). In addition to traditional statistical approaches, a novel recursive partitioning technique will be used that will allow for the detection simultaneous interactions among multiple candidate genes and smoking. This effort extends the highly productive collaborations of this team and represents among the first study to systematically examine the dual role of CD14/TLR genetic polymorphisms and smoking in RA. We anticipate that the results of this study will be extended to other RA populations. PUBLIC HEALTH RELEVANCE: Narrative (Relevance to Veterans Health): Arthritis and its allied conditions are substantially more prevalent among veterans than non-veterans, affecting more than one-third of all VA healthcare users (Dominick KL et al. J Rheumatol. 2006). Although RA affects between 0.5% and 1% of the general population and is more common in women than men, it has been estimated to affect up to 2% of VA healthcare users. Moreover, compared to RA in women, RA in men (the demographic most commonly treated in the VA) leads to greater morbidity and worse disease-related outcomes. With an aging and predominantly male veteran population, it is anticipated that corresponding disease-related morbidity, mortality, and healthcare costs will continue to rise in the VA. Cigarette smoking, common among VA healthcare users, is associated with both RA risk and worse disease expression and this association appears to be mediated by select genetic risk factors. This study will provide important insight into the association of smoking and variation in CD14/TLR pathway genes with RA disease expression in two vastly understudied RA populations, men and African Americans.